tbuckley/cabot-search huggingface dataset:
Abstract 3648: Hedgehog represses angiogenesis in PDAC through a paracrine cascade mediated by Wif1
Authors: Marie C. Hasselluhn, Amanda R. Decker, Alvaro Curiel Garcia, Carlo Maurer, Dafydd H. Thomas, Kenneth P. Olive
Journal: Cancer Research (2022)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by an extremely heterogeneous tumor microenvironment (TME) paired with a sparse and compromised vascular network. These features of the TME shape drug responses and contribute to PDAC’s distinctive chemotherapeutic resistance. Prior work demonstrated that inhibition of the Hedgehog (Hh) signaling pathway using Smoothened (Smo) inhibitors led to increased angiogenesis. However, the precise mechanisms through which the Hh pathway regulates angiogenesis has remained elusive and subsequent studies with different agents and timepoints yielded conflicting data. Frustratingly, the phenotype could not be recreated in simple co-culture models. In order to maintain the cellular heterogeneity and spatial organization that characterizes PDAC, we developed a novel tumor explant system for short-term cultures of both murine and human PDAC. Briefly, we cultured intact 300 μm slices of PDAC tissue on a modified gelatin platform system with a novel culture medium informed by the metabolic composition of PDAC tumor interstitial fluid. This system replicates some of the nutrient/waste gradient of PDAC and enables tumors to be cultured up to one week maintaining the representation of multiple cell types. Studies in explants were complemented by work in the Kras-LSL.G12D/+, p53-LSL.R172H/+, Pdx1-Cre (KPC) genetically engineered model of PDAC. Comparison of short versus long-term Smo inhibition in KPC mouse pancreatic tumors revealed a robust increase in vessel density in short-term treatment that is lost at later timepoints. Studies in murine and human PDAC explants employing different Smo inhibitors demonstrated increased endothelial tip cell formation upon two days of treatment, resulting in increased vessel density after four days. Computational analyses of human PDAC single cell RNAseq data identified candidate cellular subsets potentially involved in the signaling cascade. RNAseq of pre- and on-treatment tumor samples from KPC mice identified Wif1 as a candidate Hh pathway target gene that effected these programs. Mechanistic studies in tumor explants reveal a complex, multi-step mechanism involving several cell types that led to suppression of angiogenesis in PDAC. These studies both provide a candidate mechanism for Hh-mediated angiosuppression and also demonstrated how the tumor explant platform can elucidate complex intercellular signaling cascades in both murine and human PDAC. Citation Format: Marie C. Hasselluhn, Amanda R. Decker, Alvaro Curiel Garcia, Carlo Maurer, Dafydd H. Thomas, Kenneth P. Olive. Hedgehog represses angiogenesis in PDAC through a paracrine cascade mediated by Wif1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3648.
Abstract 2987: A versatile assay suite for the discovery of new KRAS pathway inhibitors
Authors: Ekaterina Kouznetsova, Lauren McCauley, Elaine Steinke-Neal, Timothy Sullivan, Louis Primavera, Rebecca Eells, Haiching Ma
Journal: Cancer Research (2022)

Abstract The small GTPase, KRAS, is a known oncogene and a desirable drug target due to prevalence of mutations with poor disease prognosis. The absence of good druggable binding pockets has made modulator compound discovery challenging and unsuccessful. Identification of new inhibitor target sites has led to the resurgence of interest in KRAS drug discovery. To facilitate drug discovery activities targeting KRAS/MAPK pathway, we have produced the full spectrum of pathway proteins including kinases, wild type and mutated KRAS, guanine nucleotide exchange factor and effectors. This poster will summarize our most recent assay development efforts for biochemical and biophysical assays for these targets. Citation Format: Ekaterina Kouznetsova, Lauren McCauley, Elaine Steinke-Neal, Timothy Sullivan, Louis Primavera, Rebecca Eells, Haiching Ma. A versatile assay suite for the discovery of new KRAS pathway inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2987.
Abstract 3816: Functional atlas of prostate mesenchyme
Authors: Hubert Pakula, Ryan Carelli, Nicolo Fanelli, Madhavi Jere, Caitlin Unkenholz, Mohamed Omar, Caroline Ribeiro- Fidalgo, Filippo Pederzoli, Cory Abate-Shen, David S. Rickman, Brian Robinson, Luigi Marchionni, Massimo Loda
Journal: Cancer Research (2022)

Abstract Prostate cancer has a heterogeneous prognosis, and genetic alterations alone do not fully explain clinical behavior. We previously characterized the stroma of localized human prostates by Laser Capture Microdissection, and found that stroma was substantially different in prostates with and without tumor. Furthermore, a stromal gene signature reflecting bone remodeling was upregulated in high compared to low Gleason grade cases. To determine how stromal cells contribute to carcinogenesis and progression we study whether specific genetic alterations in the epithelium induce unique stromal changes. To do this, we utilized Genetically Engineered Mouse Models (GEMMs) representing common prostate cancer mutations and compared these to their wild-type conterparts: the Tmprss2-ERG fusion knock-in murine model induces histological alterations in the stroma in the absence of an epithelial phenotype; the Pten deletion mouse model (PtenKO) results in prostate intraepithelial neoplasia (PIN) but not invasive cancer; the Hi-Myc GEMM, leads to PIN and subsequently invasion; and the Pb4-Cre +/-;Pten f/f; LSL-MYCN +/+; Rb1 f/f (MNRPDKO) mouse model that leads to neuroendocrine prostate cancer (NEPC). We generated a comprehensive single-cell transcriptomic atlas of the mouse prostate cancer mesenchyme in these models. Using deep generative modeling followed by graph-based clustering and gene regulatory network inference, six (6) distinct subsets of fibroblasts and two (2) subsets of smooth muscle cells (myofibroblasts and pericytes) were identified. Notably, some subsets were common across all GEMMs and WT mice, while others aligned with specific genotypes. Moreover, we found a variable pattern of positive and negative Ar expressing cells between genotypes. Analysis by CellphoneDB of mesenchymal-epithelial communications revealed the complex cross-talk between mutated epithelial cells and the tumor microenvironment. Multiplex immunofluorescence phenotyping of mesenchymal cell confirmed the cluster subtypes by both expression and spatial location. Finally, stromal transcripts defining mesenchymal cluster subtypes associated with Tmprss2-ERG were conserved between mouse and human genotypes.This study lays the groundwork for understanding and ultimately targeting stromal-epithelial interactions in prostate cancer. Citation Format: Hubert Pakula, Ryan Carelli, Nicolo Fanelli, Madhavi Jere, Caitlin Unkenholz, Mohamed Omar, Caroline Ribeiro- Fidalgo, Filippo Pederzoli, Cory Abate-Shen, David S. Rickman, Brian Robinson, Luigi Marchionni, Massimo Loda. Functional atlas of prostate mesenchyme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3816.
Association of Neighborhood-Level Material Deprivation With Atrial Fibrillation Care in a Single-Payer Health Care System: A Population-Based Cohort Study
Authors: Husam Abdel-Qadir, Leo E. Akioyamen, Jiming Fang, Andrea Pang, Andrew C.T. Ha, Cynthia A. Jackevicius, David A. Alter, Peter C. Austin, Clare L. Atzema, R. Sacha Bhatia, Gillian L. Booth, Sharon Johnston, Irfan Dhalla, Moira K. Kapral, Harlan M. Krumholz, Candace D. McNaughton, Idan Roifman, Karen Tu, Jacob A. Udell, Harindra C. Wijeysundera, Dennis T. Ko, Michael J. Schull, Douglas S. Lee
Journal: Circulation (2022)

Background: There are limited data on the association of material deprivation with clinical care and outcomes after atrial fibrillation (AF) diagnosis in jurisdictions with universal health care. Methods: This was a population-based cohort study of individuals ≥66 years of age with first diagnosis of AF between April 1, 2007, and March 31, 2019, in the Canadian province of Ontario, which provides public funding and prohibits private payment for medically necessary physician and hospital services. Prescription medications are subsidized for residents &gt;65 years of age. The primary exposure was neighborhood material deprivation, a metric derived from Canadian census data to estimate inability to attain basic material needs. Neighborhoods were categorized by quintile from Q1 (least deprived) to Q5 (most deprived). Cause-specific hazards regression was used to study the association of material deprivation quintile with time to AF-related adverse events (death or hospitalization for stroke, heart failure, or bleeding), clinical services (physician visits, cardiac diagnostics), and interventions (anticoagulation, cardioversion, ablation) while adjusting for individual characteristics and regional cardiologist supply. Results: Among 347 632 individuals with AF (median age 79 years, 48.9% female), individuals in the most deprived neighborhoods (Q5) had higher prevalence of cardiovascular disease, risk factors, and noncardiovascular comorbidity relative to residents of the least deprived neighborhoods (Q1). After adjustment, Q5 residents had higher hazards of death (hazard ratio [HR], 1.16 [95% CI, 1.13–1.20]) and hospitalization for stroke (HR, 1.16 [95% CI, 1.07–1.27]), heart failure (HR, 1.14 [95% CI, 1.11–1.18]), or bleeding (HR, 1.16 [95% CI, 1.07–1.25]) relative to Q1. There were small differences across quintiles in primary care physician visits (HR, Q5 versus Q1, 0.91 [95% CI, 0.89–0.92]), echocardiography (HR, Q5 versus Q1, 0.97 [95% CI, 0.96–0.99]), and dispensation of anticoagulation (HR, Q5 versus Q1, 0.97 [95% CI, 0.95–0.98]). There were more prominent disparities for Q5 versus Q1 in cardiologist visits (HR, 0.84 [95% CI, 0.82–0.86]), cardioversion (HR, 0.80 [95% CI, 0.76–0.84]), and ablation (HR, 0.45 [95% CI, 0.30–0.67]). Conclusions: Despite universal health care and prescription medication coverage, residents of more deprived neighborhoods were less likely to visit cardiologists or receive rhythm control interventions after AF diagnosis, even though they exhibited higher cardiovascular disease burden and higher risk of adverse outcomes.
OLIG2 Is a Determinant for the Relapse of <i>MYC</i>-Amplified Medulloblastoma
Authors: Zhenhua Xu, Najiba Murad, Daniel Malawsky, Ran Tao, Samuel Rivero-Hinojosa, Dörthe Holdhof, Ulrich Schüller, Peng Zhang, Christopher Lazarski, Brian R. Rood, Roger Packer, Timothy Gershon, Yanxin Pei
Journal: Clinical Cancer Research (2022)

Patients with MYC-amplified medulloblastoma (MB) have poor prognosis and frequently develop recurrence, thus new therapeutics to prevent recurrence are needed.We evaluated OLIG2 expression in a panel of mouse Myc-driven MB tumors, patient MB samples, and patient-derived xenograft (PDX) tumors and analyzed radiation sensitivity in OLIG2-high and OLIG2-low tumors in PDX lines. We assessed the effect of inhibition of OLIG2 by OLIG2-CRISPR or the small molecule inhibitor CT-179 combined with radiotherapy on tumor progression in PDX models.We found that MYC-associated MB can be stratified into OLIG2-high and OLIG2-low tumors based on OLIG2 protein expression. In MYC-amplified MB PDX models, OLIG2-low tumors were sensitive to radiation and rarely relapsed, whereas OLIG2-high tumors were resistant to radiation and consistently developed recurrence. In OLIG2-high tumors, irradiation eliminated the bulk of tumor cells; however, a small number of tumor cells comprising OLIG2- tumor cells and rare OLIG2+ tumor cells remained in the cerebellar tumor bed when examined immediately post-irradiation. All animals harboring residual resistant tumor cells developed relapse. The relapsed tumors mirrored the cellular composition of the primary tumors with enriched OLIG2 expression. Further studies demonstrated that OLIG2 was essential for recurrence, as OLIG2 disruption with CRISPR-mediated deletion or with the small-molecule inhibitor CT-179 prevented recurrence from the residual radioresistant tumor cells.Our studies reveal that OLIG2 is a biomarker and an effective therapeutic target in a high-risk subset of MYC-amplified MB, and OLIG2 inhibitor combined with radiotherapy represents a novel effective approach for treating this devastating disease.
Abstract 2974: A complex of tumor-suppressor NF1 and SPRED2 promotes pancreatic cancer tumorigenesis
Authors: Sunny Kim, Jonathan P. Kastan, Hsiu-Chi Ting, Youngkyu Park, Dave Tuveson
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with poor prognosis due to late detection and lack of effective therapeutic options. &amp;gt;90% of PDAC tumors are driven by activating mutations in the KRAS oncogene, making it an appealing subject for further investigation into understanding PDAC biology and offering a potential genetic vulnerability to target in patients. Our laboratory has previously reported a mutant-KRAS-proximal complex at the plasma membrane that consists of tumor-suppressor Neurofibromatosis type 1 (NF1), Sprouty Related EVH1 Domain Containing 2 (SPRED2), and Ribosomal S6 Kinase 1 (RSK1). This complex mechanistically suppresses WT KRAS signaling via RSK1, a suppression which is then relieved upon mutant KRAS inhibition, ultimately promoting adaptive resistance for PDAC cells under these conditions. These data highlighted a potential paradoxical role for two canonical tumor-suppressors, NF1 and SPRED2, as promoters of PDAC tumorigenesis when mutant KRAS is inhibited. We find that knockout of NF1 in PDAC organoids induces a substantial growth defect in vivo, and our preliminary data indicates that SPRED2 knockout PDAC cells have reduced proliferation in vitro. Moreover, both SPRED2 and NF1 KO promotes a diminished migratory phenotype in vitro. Given NF1's well-established role as a tumor-suppressor, our observations of decreased tumorigenic properties upon NF1 deletion are unexpected. We hypothesize that NF1 and Spred2 promote tumorigenesis via recruitment of RSK1 to the plasma membrane, inducing the phosphorylation of putative substrates to stimulate a pro-migratory cellular behavior. Our work suggests the existence of a unique RSK1 program localized at the plasma membrane by mutant KRAS, providing a new facet of oncogenesis to investigate for fundamental understanding and potential therapeutic opportunities. Citation Format: Sunny Kim, Jonathan P. Kastan, Hsiu-Chi Ting, Youngkyu Park, Dave Tuveson. A complex of tumor-suppressor NF1 and SPRED2 promotes pancreatic cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2974.
Abstract 1197: Refining the drug-gene interaction database for precision medicine pipelines
Authors: Matthew Cannon, James Stevenson, Kori Kuzma, Colin O'Sullivan, Katherine Miller, Olivia Grischow, Adam Coffman, Susanna Kiwala, Joshua F. McMichael, Dorian Morrissey, Kelsy Cotto, Obi Griffith, Malachi Griffith, Alex Wagner
Journal: Cancer Research (2022)

Abstract The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a publicly accessible resource that aggregates 102,426 gene records and 57,498 drug records from 40 drug-gene interaction data sources to aid both researchers and clinicians in identifying associations between genes of interest and available drugs and therapeutics. By using peer-reviewed data sources and publications, DGIdb represents a stand-alone resource with over 100,000 drug-gene interaction claims across 30 interaction types to drive hypothesis generation in precision medicine and interpretation pipelines. The background process that normalizes drugs to a harmonized ontological concept has been upgraded. These improvements have increased concept normalization for drugs by 20% and are now available as a stand-alone service for use (https://normalize.cancervariants.org/therapy/). Leveraging our platform’s ability to find relationships between disease-critical genes and available therapeutics, DGIdb has been used in clinical interpretation pipelines to find drugs for specific diseases with an emphasis on regulatory approval status. DGIdb now uses annotations from Drugs@FDA as an additional source to provide more accurate descriptors for market and maturity status of drugs, when available. Lastly, to enhance the annotation potential for DGIdb in precision medicine pipelines, we have updated our druggable gene category sources with an additional curated list of 2,217 genes. Used alone or in combination with existing categories-such as the heavily-utilized ‘clinically actionable’ category-this additional source will give precision medicine and interpretation pipelines the power to find concise, actionable annotations for specific diseases including pediatric cancers and epilepsy. These lists are managed and maintained as a publicly-available resource to provide up-to-date annotations on disease-associated genes as they become available. Citation Format: Matthew Cannon, James Stevenson, Kori Kuzma, Colin O'Sullivan, Katherine Miller, Olivia Grischow, Adam Coffman, Susanna Kiwala, Joshua F. McMichael, Dorian Morrissey, Kelsy Cotto, Obi Griffith, Malachi Griffith, Alex Wagner. Refining the drug-gene interaction database for precision medicine pipelines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1197.
Molecular Subtypes of Extra-pulmonary Neuroendocrine Carcinomas Identified by the Expression of Neuroendocrine Lineage-Specific Transcription Factors
Authors: Jasna Metovic, Anna La Salvia, Ida Rapa, Francesca Napoli, Nadia Birocco, Maria Pia Bizzi, Rocio Garcia-Carbonero, Libero Ciuffreda, Giorgio Scagliotti, Mauro Papotti, Marco Volante
Journal: Endocrine Pathology (2022)

Extra-pulmonary neuroendocrine carcinomas (EPNEC) represent a group of rare and heterogenous neoplasms with adverse clinical outcome. Their molecular profile is largely unexplored. Our aim was to investigate if the major transcriptional drivers recently described in high-grade pulmonary neuroendocrine carcinomas characterize distinct molecular and clinical subgroups of EPNEC. Gene expression of ASCL1, NEUROD1, DLL3, NOTCH1, INSM1, MYCL1, POU2F3, and YAP1 was investigated in a series of 54 EPNEC (including 10 cases with mixed components analyzed separately) and in a group of 48 pulmonary large cell neuroendocrine carcinomas (P-LCNEC). Unsupervised hierarchical cluster analysis classified the whole series into four major clusters. P-LCNEC were classified into two major clusters, the first ASCL1/DLL3/INSM1-high and the second (including four EPNEC) ASCL1/DLL3-low but INSM1-high. The remaining EPNEC cases were sub-classified into two other clusters. The first showed INSM1-high and alternative ASCL1/DLL3 or NEUROD1 high expression. The second was characterized mainly by MYCL1 and YAP1 overexpression. In the ten cases with mixed histology, ASCL1, DLL3, INSM1, and NEUROD1 genes were significantly upregulated in the neuroendocrine component. Higher gene-expression levels of NOTCH1 and INSM1 were associated with lower pT stage and negative nodal status. Low INSM1 gene expression was associated with shorter overall survival in the entire case series (p = 0.0017) and with a trend towards significance in EPNEC, only (p = 0.06). In conclusion, our results show that EPNEC possess distinct neuroendocrine-lineage-specific transcriptional profiles; moreover, low INSM1 gene expression represents a novel potential unfavorable prognostic marker in high-grade NECs including those in extra-pulmonary location.
Abstract 1883: Large scale viability screening with PRISM underscores non-inhibitory properties of small molecules
Authors: Lucian de Waal, Kevin Larpenteur, Li Wang, Cong Zhu, Jordan Bryan, Mustafa Kocak, Corrie Aghia, Joshua Bittker, Victor Jones, Anita Vrcic, Edward McBride, Samantha Bender, Kalea Gore, Frank Li, Zhenghao Chen, Aviad Tsherniak, Aravind Subramanian, Daphne Koller, Jeffery Settleman, Chris C. Mader, David Stokoe, Ari Firestone, Jennifer A. Roth, Todd R. Golub
Journal: Cancer Research (2022)

Abstract Oncology drug discovery has been dependent on phenotypic screening that lead to discovery of many drugs that remain essential cancer treatments to this day. Historically, logistical and technological limitations have hampered the scale of phenotypic small molecule screening across genomic diverse models. Until recently, large scale phenotypic screening across many cell lines, reflecting the somatic diversity in cancer, has not been possible. The PRISM technology does allow for a high-throughput approach to phenotypic viability screening by pooling cell lines and deconvoluting their response to small molecules using unique integrated DNA-barcodes. Here, we report on the results of a large phenotypic screening effort to identify novel small molecules and targets that can expand our knowledge on cancer vulnerabilities and can spur development of phenotypic drug discovery. A library of 18.000 compounds was assembled based on structural diversity and ability to induce gene-expression changes. Of these 18.000 compounds, around 3.500 were found to reduce cell viability of at least 5 cell lines in the PRISM assay. Of the cytotoxic compounds, we did not identify many small molecules that correlated strongly with CRISPR KO dependency data from project Achilles, and instead found that gene-expression correlations hold much more predictive value. By using additional approaches, we were able to identify the target of select novel cytotoxic small molecules and their respective mechanism-of-action. To our surprise, we have identified few compounds that act as canonical inhibitors of cancer drivers, and instead found compounds that act as molecular glues, prodrugs or inhibitors of more general cellular processes. These findings make a strong case for large scale phenotypic viability screening across genomically diverse models as a complementary approach to target identification next to target based drug discovery. Citation Format: Lucian de Waal, Kevin Larpenteur, Li Wang, Cong Zhu, Jordan Bryan, Mustafa Kocak, Corrie Aghia, Joshua Bittker, Victor Jones, Anita Vrcic, Edward McBride, Samantha Bender, Kalea Gore, Frank Li, Zhenghao Chen, Aviad Tsherniak, Aravind Subramanian, Daphne Koller, Jeffery Settleman, Chris C. Mader, David Stokoe, Ari Firestone, Jennifer A. Roth, Todd R. Golub. Large scale viability screening with PRISM underscores non-inhibitory properties of small molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1883.